Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibers. Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes such as Congo Red, and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common x-ray diffraction and infrared spectra.
Some amyloidotic diseases can be idiopathic but most of these diseases appear as a complication of a previously existing disorder. For example, primary amyloidosis can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma. Secondary amyloidosis is usually seen associated with chronic infection such as tuberculosis, or chronic inflammation such as rheumatoid arthritis. A familial form of secondary amyloidosis is also seen in the Familial Mediterranean Fever (FMF). This familial type of amyloidosis, like the other types of familial amyloidosis, is genetically inherited and is found in specific group populations. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis (BSE), Creutzfeldt-Jakob disease, and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by congophilic cerebral angiopathy, neuritic plaques and neurofibrillary tangles. In this case, the plaque and blood vessel amyloid is formed by the deposition of fibrillar Aβ amyloid protein. Other systemic diseases such as adult-onset diabetes, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systemically. Yet another amyloid-associated disease is cerebral amyloid angiopathy. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition.
Each amyloidogenic protein can organize into β-sheets and form insoluble fibrils which get deposited extracellularly. Each amyloidogenic protein, although completely different in nature, has the same property of forming fibrils and binding to other elements such as proteoglycan (glycosaminoglycan, or “GAG”), amyloid P, and complement component. Moreover, each amyloidogenic protein has amino acid sequences which, although different, will show similarities such as regions (referred to as the GAG binding site) with the ability to bind to GAGs, as well as other regions which promote β-sheet formation.
In specific cases, once amyloidotic fibrils are deposited, they become toxic to the surrounding cells. Aβ fibrils organized as senile plaques have been shown to be associated with dead neuronal cells and microgliosis in patients with Alzheimer's disease. When tested in vitro, fibrillar Aβ peptide has been shown to be capable of triggering an activation process of the microglia (brain macrophages) in vitro which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer's disease.
In another type of amyloidosis seen in patients with Type II diabetes, the amyloidogenic protein IAPP has been shown to induce β-islet cell toxicity in vitro. Hence, appearance of IAPP fibrils in the pancreas of Type II diabetic patients could contribute to the loss of the β islet cells (Langerhans), and organ dysfunction.
Diagnostic medical imaging has become a critical element of modern health care. Ultrasound, radionuclide, x-ray, and magnetic resonance imaging techniques facilitate the diagnosis of disease. Each of these techniques expose a body to an energy source, e.g., sound, x-rays, radiation (either from an internal source, e.g., a radioactive pharmaceutical, or an external source), radio waves, etc., and monitor the characteristics of that energy as it interacts with the body. Diagnostic pharmaceuticals, frequently called contrast agents, may be simultaneously administered to a patient to augment the usefulness of the imaging technique itself by altering the energy or the way that energy interacts with tissues. Diagnostic medical imaging frequently uses targeted contrast agents that, in binding or localizing at sites selectively within the body, help to resolve an image of diagnostic interest. Targeted diagnostic imaging contrast agents generally consist of a targeting moiety labeled with a traceable moiety. Such traceable moieties include fluorescent tags; radio-opaque dyes (e.g., iodinated aromatics), radioactive elements such as 3H, 18F, 125I, 129I; or diagnostically useful chelated radioactive or paramagnetic metals such as Gd(III), Mn(II), Tc-99m, Re-186, Re-188, In-111, or Ga-67. The targeting moiety carries the label to the site of diagnostic interest where it is detected, e.g., by MRI, US, CT, or radionuclide imaging (including SPECT).